Introduction

The conceptual landscape of innate immunology has undergone a transformative evolution over the last three decades, shifting from a binary self/non‐self‐discrimination model to a multifaceted “danger” surveillance network. This paradigm shift began in 1989, when Charles Janeway proposed the concept of Pathogen‐Associated Molecular Patterns (PAMPs) [1]. PAMPs are defined as evolutionarily conserved, invariant molecular signatures, such as lipopolysaccharides (LPS) or double‐stranded RNA (dsRNA), that are unique to microorganisms and recognized by germline‐encoded pattern recognition receptors (PRRs).To address the limitations of the PAMP model in explaining sterile inflammation where PAMPs are absent, Polly Matzinger introduced the Danger Theory in 1994 [2], formalizing the role of damage‐associated molecular patterns (DAMPs), which were later defined by Water Land in 2003 [3]. Unlike PAMPs, DAMPs are endogenous molecules normally sequestered within healthy cells or tissues that are liberated into the extracellular milieu following cellular stress or cell death, thereby alerting the host to internal threats regardless of microbial presence. This nomenclature was further refined in 2005 by Joost Oppenheim, who introduced the term “alarmins” to describe a specific subset of endogenous mediators, such as HMGB1 and defensins, that are rapidly released upon tissue injury to recruit and activate immune cells [4]. Although distinct in their historical origins, the terms DAMPs and alarmins are utilized synonymously in the vast majority of current literature. Consequently, this review will incorporate alarmins into a unified narrative under the broader DAMP category to provide a more cohesive structural framework.

While PAMPs and DAMPs originate from distinct exogenous or endogenous sources, they are fundamentally interconnected, often converging on shared signaling pathways to coordinate the host's defensive and reparative programs. Crucially, these danger signals do not operate in isolation; rather, their functions are intricately intertwined, with PAMPs and DAMPs engaging in complex bidirectional crosstalk that shapes immune responses. Under physiological conditions, these signals facilitate the clearance of pathogens and debris and maintain homeostatic equilibrium [5]. However, their aberrant accumulation under pathological conditions drives the progression of diverse disorders, including chronic infections, autoimmune diseases, and malignancy [6]. In recent years, the scope of danger signal biology has expanded beyond these classical roles into revolutionary new frontiers. Recent evidence has positioned PAMPs and DAMPs as central architects of trained immunity [7, 8], a form of innate immune memory where primary exposure to these signals induces long‐term functional reprogramming through sustained metabolic and epigenetic modifications. Furthermore, these molecules are now recognized as essential mediators of cross‐organ crosstalk, functioning as systemic danger signals that traverse physiological barriers to communicate inflammatory status between disparate anatomical compartments, such as the gut–liver or brain–bone axes [9]. In addition, the therapeutic potential of targeting PAMP and DAMP pathways has garnered increasing attention [10]. Strategies range from inhibiting PAMP and DAMP signaling for controlling inflammatory response to harnessing their immunostimulatory properties for vaccination and cancer immunotherapy.

To synthesize contemporary advancements, we critically evaluated English‐language literature concerning PAMPs and DAMPs published within the last five years across databases such as PubMed and EMBASE. Building upon this foundational literature, this review provides an in‐depth analysis of PAMP and DAMP molecular characterization, subcellular sensing, and regulatory networks. We further examine their multifaceted pathological roles and the clinical progress in therapeutic development, ultimately bridging the gap between basic biology of danger signals and translational applications (Figure 1).

FIGURE 1: Integrative conceptual framework of PAMP and DAMP biology. The schematic illustrates the biological progression, regulatory networks, and clinical implications of danger signals. (1) Generation: Exogenous PAMPs originate from microbial components, while endogenous DAMPs are liberated via cellular stress or extracellular matrix (ECM) remodeling. (2) Sensing: These signals are detected by specialized sentinel cells equipped with pattern recognition receptors (PRRs) and non‐PRRs. (3) Effect: PAMPs and DAMPs function either independently or through dynamic interplay (synergy and antagonism) to regulate immune responses, remodel the stromal microenvironment, and drive systemic crosstalk. These signaling cascades are tightly calibrated: PAMP signaling is shaped by the tension between pathogen evasion tactics and host dynamic tuning, whereas DAMP signaling is strictly controlled at the levels of generation, clearance, and receptor sensing thresholds. The ultimate biological trajectory toward human disease is dictated by contextual influence factors. Translating these mechanistic insights facilitates the application of PAMPs and DAMPs as clinical biomarkers and guides the development of bidirectional targeted therapies for immune modulation.